This invention relates to absorbable implants for delivering a biochemical agent into the system of an animal in a sustained release over a period of time. Various biochemical agents are conveniently administered to animals by means of subcutaneous implants of pellets which comprise the active biochemical agent and a biocompatible, absorbable excipient. Such biochemical agents which have been administered by means of subcutaneous implants include hormones and anabolic agents for improving growth and feed efficiency in cattle, sheep, pigs and fowl. It is also contemplated that various biochemical agents requiring sustained release can be implanted in horses, dogs, cats, other domestic animals, zoo animals and, in some situations, in wild animal populations. Controlled release of certain hormones can be used to control ovulation in cattle and sheep to schedule breeding programs.
Subcutaneous implanting is advantageous over ad libitum feeding of many biochemical agents because it ensures that a sustained effective dosage of the active biochemical agent is administered to each animal. It is convenient to implant animals such as cattle and sheep on the ear because the pellet is less likely to be dislodged by the animal, and the ear can be discarded when the animal is marketed.
The excipient used in the implant pellet is an important factor in the physiological effect obtained. It should be biocompatible, and nonirritating and dissolve completely without encapsulation to release the active biochemical agent at the desired release rate.
Lactose has long been used as an excipient for implant pellets, and in tablets and pills. Lactose is relatively tasteless, and it is biocompatible. Lactose excipients have been used to administer anabolic agents, such as are described in U.S. Pat. No. 3,196,019 issued July 20, 1965. The active ingredient and the lactose are blended together and pelleted into small spheres or cylindrical shapes containing the desired dosage. Pelleting is conveniently performed on a rotary tableting machine having the appropriate die inserts. The Model B-2 Stokes rotary tableting machine has been used for this purpose to produce pellets having a hardness in the range of 5-10 Strong-Cobb Hardness Units (SCHU).
An implant formulation having a carrier comprising beeswax, zinc stearate, dibutylphthalate (DBP) and polyvinylpyrrolidone (PVP) is described in U.S. Pat. No. 3,428,729. The "DMP" compound is said to be the key to slow the melting of the beeswax and "PVP" and, therefore, to the controlled release of the active ingredient (a hormone to regulate ovulation).
U.S. Pat. No. 3,499,445 is also directed to ovulation control by subcutaneous implant, and describes a 3-layered compressed disc implant pellet which contains chloesterol, carbowax and magnesium stearate as the carrier material for certain steroid compounds. The object again is to obtain a sustained release of the active steroid compound from the composite disc implant. This patent also discloses surgical removal of the implants after 14-18 days to abruptly terminate the treatment.
A polylactide carrier/binder for use in combination with drugs in the form of an implant is described in U.S. Pat. No. 3,773,919 issued Nov. 20, 1973 (See U.S. Pat. No. 3,773,919, column 9, line 59). The term "polylactide" includes a polyester derived from an .alpha.-hydroxycarboxylic acid and more specifically, the polymer derived from lactic acid (.alpha.-hydroxypropionic acid). The above carrier material is said to undergo biodegradation in the body into normal metabolic products.
An extensive discussion of various types of implant pellets is found in U.S. Pat. No. 4,180,560 issued Dec. 25, 1979. This patent is directed to a biocompatible, inert core implant having a biosoluble coating comprising a carrier such as polyethylene glycol (PEG) and cholesterol. The inert core materials listed include glass, cellulose acetate, methylmethacrylate, other acrylics, nylon, polypropylene, silicone rubber, PEG and sugar-starch beads.
A fibrin prosthesis useful in surgical procedures is described in U.S. Pat. No. 3,523,807 issued Aug. 11, 1970. The fibrin was obtained from blood plasma by natural clotting through the addition of calcium chloride solution. The clotted plasma was ground and the serum pressed out, and the ground product is washed and dried to provide a fibrin powder. The fibrin powder can be molded into various shapes to be used in surgical procedures such as to strengthen liver-sutures, provide a temporary cap for use in a hip-joint operation and to elevate the urethra in a urogenital surgical procedure.
Bovine fibrin is disclosed as being used for these surgical purposes by Capperauld, et al., Properties of Bovine Fibrin Absorbable Implants, Surgery, Gynecology and Obstetrics, Volume 144, pages 3-7 (January 1977). A method of making the fibrin is disclosed which utilizes bovine plasma by first precipitating fibrinogen with ethanol at a low temperature, following a fractional precipitation procedure. The fibrinogen is redissolved and converted into a stabilized fibrin clot by adding calcium chloride. The clot is then minced, washed, purified, pulverized and dried at 150.degree. C. to produce a bovine fibrin powder for the surgical uses described.